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Abstract

Introduction

The aim of this study was to assess cancer incidence in childhood-onset systemic lupus
erythematosus (SLE).

Methods

We ascertained cancers within SLE registries at 10 pediatric centers. Subjects were
linked to cancer registries for the observational interval, spanning 1974 to 2009.
The ratio of observed to expected cancers represents the standardized incidence ratio
(SIR) or relative cancer risk in childhood-onset SLE, versus the general population.

Results

There were 1020 patients aged <18 at cohort entry. Most (82%) were female and Caucasian;
mean age at cohort entry was 12.6 years (standard deviation (SD) = 3.6). Subjects
were observed for a total of 7,986 (average 7.8) patient-years. Within this interval,
only three invasive cancers were expected. However, 14 invasive cancers occurred with
an SIR of 4.7, 95% confidence interval (CI) 2.6 to 7.8. Three hematologic cancers
were found (two non-Hodgkin’s lymphoma, one leukemia), for an SIR of 5.2 (95% CI 1.1
to 15.2). The SIRs stratified by age group and sex, were similar across these strata.
There was a trend for highest cancer occurrence 10 to 19 years after SLE diagnosis.

Conclusions

These results suggest an increased cancer risk in pediatric onset SLE versus the general
population. In absolute terms, this represents relatively few events. Of note, risk
may be highest only after patients have transferred to adult care.

Introduction

In the past decade, there have been several large studies elucidating cancer risk
in adults with systemic lupus erythematosus (SLE). However, relatively little is known
about cancer risk in childhood-onset SLE. This knowledge gap is important since pediatric
patients have a long disease duration and a heavy burden of severity. Moreover, extrapolations
from adult-onset SLE populations are inappropriate, given the drastic clinical differences
(in disease activity, treatment, organ involvement, and so forth) between pediatric-onset
SLE and adult-onset SLE [1-3].

Our objective was to assess the observed cancer incidence in a large clinical cohort
of pediatric-onset SLE patients. We compared the observed number of cancers over the
observation interval with that which would be expected based on age-specific and sex-specific
general population cancer incidence rates.

Follow-up was calculated from the date first seen at the clinic with an SLE diagnosis
and the first of three possible events: death, cancer, or end of study interval (December
2009). We pooled observed cancers and person-years of observation. The cancers expected
to occur were calculated by multiplying the person-years in the cohort by the geographically
matched age-specific, sex-specific, and calendar year-specific cancer rates, obtained
from the same cancer registries that performed the cohort linkages. The ratio of observed
to expected cancers represents the standardized incidence ratio (SIR), or the relative
cancer risk in pediatric-onset SLE, versus the general population. In situ cancers occurring in the SLE cohort were excluded, since these lesions are generally
not included in general population cancer rates.

We provided estimates for total cancer and for hematological cancers (the most common
cancer type, and the one most often noted in prior case reports). We also present
results stratified by sex, age group, and SLE duration.

Results

There were 1,020 patients aged <18 at cohort entry. Most patients (82%) were female
and Caucasian; the mean age at cohort entry was 12.6 years (standard deviation = 3.6).
Subjects were observed for a total of 7,986 (average 7.8) patient-years. Within this
observation interval, only three invasive cancers were expected; however, 14 invasive
cancers occurred (SIR = 4.7, 95% confidence interval (CI) = 2.6, 7.8). The SIRs stratified
by age group and sex were similar across strata (Table 1). There was a trend for highest cancer occurrence within the period 10 to 19 years
after SLE diagnosis.

At the time of cancer diagnosis, mean SLE duration was 12.3 years (range 2 months,
25.2 years). We performed a sensitivity analysis excluding cancers that occurred within
the first year of SLE diagnosis (since in these cases the SLE-like manifestations
may have actually represented a paraneoplastic syndrome); here, the overall cancer
SIR was 3.0 (95% CI = 2.3, 7.8).

Three hematologic cancers were found (two non-Hodgkin’s lymphoma, one leukemia), for
an SIR of 5.2 (95% CI = 1.1, 15.2). The ages of the SLE patients (one male, one female)
at lymphoma diagnosis were 16 and 28 years, and the leukemia case was female and diagnosed
at age 7. The leukemia case and one Non-Hodgkin’s lymphoma were reported within the
first year of SLE diagnosis.

The precision of the CIs was less when the SIRs were generated by sex strata (hematological
cancer SIR for males = 7.6, 95% CI = 0.2, 42.3; and for females = 4.5, 95% CI = 0.5,
16.2). Similarly wide CIs were seen with the SIR for hematological cancers for the
age group 0 to 19 (SIR = 7.7, 95% CI = 0.9, 27.7) and for the age group 20+ (SIR = 3.2,
95% CI = 0.2, 17.5). The nonhematological cancers included one cancer each of the
bladder, brain, breast, and thyroid, three head and neck cancers, and four unspecified
cancers. The head and neck malignancy types included one cancer of the lingual tonsil
and the other two were squamous cell carcinomas not otherwise specified.

Discussion

This study compared the cancer risk in pediatric-onset SLE patients with age-specific
and sex-specific regional general population cancer rates. These results suggest an
increased cancer risk in pediatric-onset SLE versus the general population, which
appeared to be driven in part by hematological malignancies. Of course, in absolute
terms, this still translates into relatively few events (1.75 incident cancers per
1,000 person-years), which is somewhat reassuring. A limitation of this study is that
patients may have developed cancer after relocating to another state or province,
thus under-representing the true cancer incidence in this cohort. Another limitation
is that we are unable to comment on the relative importance of SLE disease itself,
versus therapeutic drugs. We are also unable to evaluate the effects of race/ethnicity,
or of SLE clinical factors such as type of organ involvement and disease severity.

Our study adds substantially to the pre-existing scant literature regarding malignancies
in pediatric-onset rheumatic diseases. There are a few published case reports of malignancy
occurring after the onset of pediatric-onset SLE [4-6] and these four case reports all document hematological malignancies: Hodgkin’s lymphoma,
mucosa-associated lymphoid tissue lymphoma, Burkitt’s lymphoma, and acute lymphoblastic
leukemia (ALL). The first three cases mentioned occurred in teenagers after several
years of SLE duration, while the fourth case, which was ALL, occurred in a 6 year
old within the first year of SLE diagnosis. In addition, two additional case reports
document the simultaneous presentation of pediatric-onset SLE (fulfilling ACR criteria)
and ALL, at ages 3 and 7 [7,8].

This possibly suggests a bimodal pattern to hematological malignancies in pediatric-onset
SLE. The first phase of this bimodal pattern would correspond to the scenario of a
young pediatric-onset SLE patient presenting with pancytopenia, where leukemia (for
example, ALL) is a possible consideration. The second part of this bimodal pattern
of hematological cancer risk in pediatric-onset SLE seems to be related to lymphoma
(both Hodgkin’s lymphoma and non-Hodgkin’s lymphoma) in older individuals. Alternatively,
the first peak might actually represent, at least in part, paraneoplastic presentations
masquerading as pediatric-onset SLE; in either case, clinicians should remain vigilant
to the possibility of a disease like ALL in such a setting.

Ours is the first cohort study of the cancer experience of a large number of patients
with pediatric-onset SLE, comparing the observed number of cancers with those expected
(based on age, sex, and calendar-year appropriate rates for the geographically relevant
general population). In terms of a comparison with what is known in adults, an increased
hematologic cancer risk (especially Non-Hodgkin’s lymphoma) has also been demonstrated
in adult-onset SLE. Interestingly, in adult-onset SLE the highest cancer risk, relative
to the general population, occurs in the youngest age group (<45 years) [9].

There is currently also interest in malignancy risk for other pediatric-onset rheumatic
diseases, including juvenile idiopathic arthritis. Using similar methods to the current
study, we found rather different results in juvenile idiopathic arthritis, for overall
cancer, with six cancers observed and seven expected, leading to an overall SIR that
was not elevated (SIR = 0.8, 95% CI = 0.3, 1.8) [10]. However, all cancers were hematologic, including five leukemia cases. This potentially
represents a signal for a potentially increased risk of hematological cancer in JIA,
similar to what we present here in pediatric-onset SLE. The etiology of this potentially
increased risk of hematological malignancies in juvenile idiopathic arthritis also
remains to be elucidated.

Conclusions

This study represents the most up-to-date results from our multicenter initiative
to clarify baseline cancer risk in pediatric-onset SLE. There is a possible increased
risk in overall cancer, which may be driven by hematologic cancer risk. Further work
in progress will compare risk across geography, race/ethnicity, and disease subset.

Abbreviations

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

SB, AEC, EvS, LES, EDS, HIB, KAH, RQC, KMO, KO, AMR, CMD, MK, and RR-G contributed
to the study design, data collection, data analysis, and interpretation and preparation
of results. JL contributed to data preparation, data analysis and interpretation and
presentation of results. LJ contributed to statistical analysis and the interpretation
and preparation of the results. JLL and EMT participated in the design and coordination,
and helped to draft the manuscript. In addition, all authors revised the manuscript
and approved the final version.

Acknowledgements

This study is funded by the Canadian Institutes of Health MOP-106431 and the National
Institutes of Health 5R03CA149970-2.